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Lancet Glob Health. 2019 May;7(5):e568-e584. doi: 10.1016/S2214-109X(19)30076-2.

The incidence, aetiology, and adverse clinical consequences of less severe diarrhoeal episodes among infants and children residing in low-income and middle-income countries: a 12-month case-control study as a follow-on to the Global Enteric Multicenter Study (GEMS).

Author information

1
University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: kkotloff@som.umaryland.edu.
2
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
3
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA.
4
Centre pour le Développement des Vaccins, Bamako, Mali.
5
National Institute of Cholera and Enteric Diseases, Kolkata, India.
6
Department of Paediatrics and Child Health, the Aga Khan University, Karachi, Pakistan.
7
International Centre for Diarrhoeal Disease Research, Mohakhali, Dhaka, Bangladesh.
8
Medical Research Council Unit The Gambia at The London School of Hygiene & Tropical Medicine, Banjul, The Gambia.
9
Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique; Barcelona Institute for Global Health, Barcelona, Spain; Barcelona Center for International Health Research, Barcelona, Spain; Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
10
Medical Research Council Unit The Gambia at The London School of Hygiene & Tropical Medicine, Banjul, The Gambia; Division of Microbiology & Immunity, Warwick Medical School, University of Warwick, Coventry, UK.
11
Centro de Investigação em Saúde da Manhiça, Maputo, Mozambique; Instituto Nacional de Saúde, Ministério da Saúde, Maputo, Mozambique.
12
Department of Veterans Affairs, Cooperative Studies Program Coordinating Center, Perry Point, MD, USA.
13
Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands.
14
Centre for Intervention Science in Maternal and Child Health, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Norwegian Institute of Public Health, Oslo, Norway.
15
University of Maryland School of Medicine, Baltimore, MD, USA.
16
Department of Microbiology and Immunology, The University of Melbourne, Parkville, VIC, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia.

Abstract

BACKGROUND:

Diarrheal diseases remain a leading cause of illness and death among children younger than 5 years in low-income and middle-income countries. The Global Enteric Multicenter Study (GEMS) has described the incidence, aetiology, and sequelae of medically attended moderate-to-severe diarrhoea (MSD) among children aged 0-59 months residing in censused populations in sub-Saharan Africa and south Asia, where most child deaths occur. To further characterise this disease burden and guide interventions, we extended this study to include children with episodes of less-severe diarrhoea (LSD) seeking care at health centres serving six GEMS sites.

METHODS:

We report a 1-year, multisite, age-stratified, matched case-control study following on to the GEMS study. Six sites (Bamako, Mali; Manhiça, Mozambique; Basse, The Gambia; Mirzapur, Bangladesh; Kolkata, India; and Bin Qasim Town, Karachi, Pakistan) participated in this study. Children aged 0-59 months at each site who sought care at a sentinel hospital or health centre during a 12-month period were screened for diarrhoea. New (onset after ≥7 diarrhoea-free days) and acute (onset within the previous 7 days) episodes of diarrhoea in children who had sunken eyes, whose skin lost turgor, who received intravenous hydration, who had dysentery, or who were hospitalised were eligible for inclusion as MSD. The remaining new and acute diarrhoea episodes among children who sought care at the same health centres were considered LSD. We aimed to enrol the first eight or nine eligible children with MSD and LSD at each site during each fortnight in three age strata: infants (aged 0-11 months), toddlers (aged 12-23 months), and young children (aged 24-59 months). For each included case of MSD or LSD, we enrolled one to three community control children without diarrhoea during the previous 7 days. From patients and controls we collected clinical and epidemiological data, anthropometric measurements, and faecal samples to identify enteropathogens at enrolment, and we performed a follow-up home visit about 60 days later to ascertain vital status, clinical outcome, and interval growth. Primary outcomes were to characterise, for MSD and LSD, the pathogen-specific attributable risk and population-based incidence values, and to assess the frequency of adverse clinical consequences associated with these two diarrhoeal syndromes.

FINDINGS:

From Oct 31, 2011, to Nov 14, 2012, we recruited 2368 children with MSD, 3174 with LSD, and one to three randomly selected community control children without diarrhoea matched to cases with MSD (n=3597) or LSD (n=4236). Weighted adjusted population attributable fractions showed that most attributable cases of MSD and LSD were due to rotavirus, Cryptosporidium spp, enterotoxigenic Escherichia coli encoding heat-stable toxin (with or without genes encoding heat-labile enterotoxin), and Shigella spp. The attributable incidence per 100 child-years for LSD versus MSD, by age stratum, for rotavirus was 22·3 versus 5·5 (0-11 months), 9·8 versus 2·9 (12-23 months), and 0·5 versus 0·2 (24-59 months); for Cryptosporidium spp was 3·6 versus 2·3 (0-11 months), 4·3 versus 0·6 (12-23 months), and 0·3 versus 0·1 (24-59 months); for enterotoxigenic E coli encoding heat-stable toxin was 4·2 versus 0·1 (0-11 months), 5·2 versus 0·0 (12-23 months), and 1·1 versus 0·2 (24-59 months); and for Shigella spp was 1·0 versus 1·3 (0-11 months), 3·1 versus 2·4 (12-23 months), and 0·8 versus 0·7 (24-59 months). Participants with both MSD and LSD had significantly more linear growth faltering than controls at follow-up.

INTERPRETATION:

Inclusion of participants with LSD markedly expands the population of children who experience adverse clinical and nutritional outcomes from acute diarrhoeal diseases. Since MSD and LSD have similar aetiologies, interventions targeting rotavirus, Shigella spp, enterotoxigenic E coli producing heat-stable toxin, and Cryptosporidium spp might substantially reduce the diarrhoeal disease burden and its associated nutritional faltering.

FUNDING:

Bill & Melinda Gates Foundation.

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